- FIGURE 1
Study design and participant inclusion. a) Study design. This was a randomised, placebo-controlled, double-blind, six-sequence, three-period, crossover study. b) Study disposition. Of 129 screened for enrolment in this study, 37 patients were randomised to one of six treatment sequences (each consisting of three treatment periods) in an allocation ratio of 1:1:1:1:1:1. For each sequence, a) six patients were planned to be randomised; b) as 37 patients were randomised, sequence 1 contained seven patients. 34 patients completed all three treatment periods. IND: indacaterol acetate; GLY: glycopyrronium bromide; MF: mometasone furoate. #: primary end-point mean forced expiratory volume in 1 s (FEV1) (L) (area under the curve from 0 to 24 h); ¶: two patients discontinued from the study during treatment period 1 due to subject/guardian decision; +: one patient experienced an asthma exacerbation and discontinued from the study on the first day of treatment period 3.
- FIGURE 2
Effect of morning or evening dosing of inhaled indacaterol acetate (IND)/glycopyrronium bromide (GLY)/mometasone furoate (MF) on weighted mean forced expiratory volume in 1 s (FEV1) (area under the curve from 0 to 24 h (AUC0–24h)) versus placebo (pharmacodynamics (PD) analysis set). Comparison of morning or evening dosing of IND/GLY/MF on weighted mean FEV1 (mL) (AUC0–24h) with placebo in the PD analysis set. Parameters were analysed using a mixed model adjusting for period, treatment and sequence as fixed effect factors, and patient as a random effect. Data are presented as least squares means treatment difference (90% CI) compared with placebo. ref: reference.
- FIGURE 3
Effect of indacaterol acetate (IND)/glycopyrronium bromide (GLY)/mometasone furoate (MF) on overall mean peak expiratory flow (L·min−1) (90% CI) over days 2–14 by treatment (pharmacodynamics analysis set). Parameters were calculated using a mixed-effects model including period, treatment (IND/GLY/MF morning, IND/GLY/MF evening, placebo), and sequence as fixed effects. Note: if a treatment period for an individual patient exceeded 14 days, the patient's peak expiratory flow (PEF) values contributed only up to day 14 for the respective period.
- TABLE 1
Definition of treatment sequences
Treatment period 1 Treatment period 2 Treatment period 3 1 A B C 2 B A C 3 C B A 4 C A B 5 A C B 6 B C A A: indacaterol acetate (IND)/glycopyrronium bromide (GLY)/mometasone furoate (MF) evening dose: placebo (a.m.) and IND/GLY/MF (p.m.); B: IND/GLY/MF morning dose: IND/GLY/MF (a.m.) and placebo (p.m.); C: placebo: placebo (a.m.) and placebo (p.m.).
- TABLE 2
Baseline participant demographics and characteristics (pharmacodynamics analysis set)
Participants 37 Age years 46.0 (18–72) Male 21 (56.8) Body mass index kg·m−2 26.2±4.67 Blood eosinophils ×109 cells·L−1 0.242±0.1588 Race White 35 (94.6) Other 2 (5.4) Screening ICS category Low-dose 31 (83.8) Medium-dose 6 (16.2) Pre-bronchodilator FEV1 L 2.9±0.72 Post-bronchodilator FEV1 L 3.4±0.81 FEV1 pre-dose % predicted 75.8 (60–96) Reversibility L 0.5±0.21 Reversibility % 18.9 (12–52) Baseline morning# PEF L·min−1 422.4±107.42 Baseline evening# PEF L·min−1 454.9±107.51 Data are presented as n, mean (range), n (%) or mean±sd. ICS: inhaled corticosteroids; FEV1: forced expiratory volume in 1 s; PEF: peak expiratory flow. #: morning and evening PEF are defined as the first adequate results prior to dosing for each time point.
- TABLE 3
Comparison of peak expiratory flow (PEF) measured in the morning and evening after 14 days of treatment (pharmacodynamics analysis set)
PEF L·min−1 LS means (90% CI) LS means difference (90% CI) Morning mean IND/GLY/MF a.m. versus placebo# 489.6 (456.2–523.1) versus 417.5 (384.1–450.9) 72.1 (61.3–82.9) IND/GLY/MF p.m. versus placebo# 504.4 (471.0–537.9) versus 417.5 (384.1–450.9) 86.9 (76.1–97.8) IND/GLY/MF a.m. versus IND/GLY/MF p.m. 489.6 (456.2–523.1) versus 504.4 (471.0–537.9) –14.8 (–25.6––4.1) Evening mean IND/GLY/MF a.m. versus placebo# 522.0 (488.7–555.4) versus 449.0 (415.7–482.3) 73.1 (61.9–84.2) IND/GLY/MF p.m. versus placebo# 507.7 (474.3–541.0) versus 449.0 (415.7–482.3) 58.7 (47.5–69.9) IND/GLY/MF a.m. versus IND/GLY/MF p.m. 522.0 (488.7–555.4) versus 507.7 (474.3–541.0) 14.4 (3.3–25.5) n=35, unless otherwise stated. Morning PEF assessments were performed 24 h after the last morning dose and 12 h after the last evening dose. Analogously, the evening PEF assessments were performed 24 h after the last evening dose and 12 h after the last morning dose. LS: least squares; IND: indacaterol acetate; GLY: glycopyrronium bromide; MF: mometasone furoate. #: n=36.
- TABLE 4
Incidence of treatment-emergent adverse events by preferred MedDRA term affecting >5% of patients (safety analysis set)
IND/GLY/MF a.m. IND/GLY/MF p.m. Placebo Total Patients 35 35 36 37 Number of patients with ≥1 adverse event 18 (51.4) 23 (65.7) 18 (50.0) 32 (86.5) Headache 5 (14.3) 3 (8.6) 7 (19.4) 10 (27.0) Nasopharyngitis 2 (5.7) 2 (5.7) 5 (13.9) 8 (21.6) Oropharyngeal pain 3 (8.6) 4 (11.4) 2 (5.6) 7 (18.9) Cough 1 (2.9) 2 (5.7) 1 (2.8) 4 (10.8) Dysphonia 2 (5.7) 3 (8.6) 1 (2.8) 4 (10.8) Asthma 1 (2.9) 1 (2.9) 1 (2.8) 3 (8.1) Throat clearing 1 (2.9) 1 (2.9) 0 (0.0) 2 (5.4) Data are presented as n or n (%). MedDRA: Medical Dictionary for Regulatory Activities; IND: indacaterol acetate; GLY: glycopyrronium bromide; MF: mometasone furoate.
Supplementary Materials
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Supplementary material 00425-2020.SUPPLEMENT
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